MDM2 Inhibitor AMG-232 and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of MDM2 inhibitor AMG-232 (AMG 232) in combination
with standard-dose radiotherapy in soft tissue sarcoma (STS) in two separate patient cohorts
(A, extremity or body wall; B, abdomen/pelvis/retroperitoneum).

II. To determine the maximum tolerated dose/recommended phase II dose (maximum tolerated
dose/recommended phase 2 dosage [MTD/RP2D]) of AMG 232 in combination with radiotherapy.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To determine % necrosis and pathologic
complete response (pCR) in final surgical resection specimen.

III. To determine % local failure (LF), disease free survival (DFS) and overall survival (OS)
at 2 years.

IV. To determine pharmacodynamics (PD) effects of AMG 232 when combined with radiotherapy by
assessing serial serum macrophage inhibitory cytokine (MIC)-1 levels.

V. To determine AMG 232 exposure (pharmacokinetics)-response relationships (PD, toxicity, and
efficacy).

TERTIARY OBJECTIVES:

I. To determine tumor volume changes determined by magnetic resonance imaging (MRI) or
computed tomography (CT) with and without contrast pre- and post-radiotherapy.

II. To characterize clinical outcomes in patients treated with AMG 232 by genomic biomarkers.

III. To determine the correlation between mdm2/4 expression determined by next-generation
sequencing (NGS) and the protein levels by immunohistochemistry (IHC).

IV. To explore the possibility of identifying tumor genetic mutations in (1) cell-free (cf)
circulating tumor deoxyribonucleic acid (ctDNA), (2) deoxyribonucleic acid/ribonucleic acid
(DNA/RNA) isolated from exosomes, and determine the concordance of these results and that
from NGS.

OUTLINE: This is a dose escalation study.

Patients receive MDM2 inhibitor AMG-232 orally (PO) on day 2, days 2 and 4, days 2-4, days
2-5, or days 1-5 of weeks -1 to 5. Patients also undergo radiation therapy daily on weeks
1-5. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and
then at 2.5 years.

Inclusion Criteria:

- PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

- Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high
grade) soft tissue sarcoma with size >= 5 cm are eligible to enroll if the intention
to treat is curative; they must have sufficient tissue to submit to central laboratory
for review as well as for NGS sequencing (see submission requirement); availability of
tumor tissue is mandatory for study eligibility; the patient must have consented to
provide archived formalin-fixed paraffin-embedded tumor tissue for future central
pathology review, NGS sequencing and/or translational research

- Appropriate stage for study entry based on the following diagnostic workup:

- History/physical examination within 30 days prior to registration;

- Imaging of the primary tumor by MRI and/or computed tomography (CT) with and
without contrast and/or positron emission tomography (PET)/CT within 60 days
prior to registration;

- Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis
within 60 days prior to registration

- There is a planned definitive surgical resection of the primary tumor

- Eastern Cooperative Oncology Group (ECOG) or Zubrod performance status of 0-1 within
30 days prior to registration

- Absolute neutrophil count >= 1500/uL within 30 days prior to registration

- Platelet count >= 100,000/uL within 30 days prior to registration

- Hemoglobin: >= 8 g/dL (no transfusions within 7 days) within 30 days prior to
registration

- Calculated creatinine clearance >= 60 ml/min (by Cockroft-Gault formula) within 30
days prior to registration

- The patient has an adequate coagulation function as defined by international
normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) or prothrombin time (PT)
=< 1.5 x ULN, and partial thromboplastin time (PTT or aPTT) =< 1.5 x ULN (those
receiving anticoagulation therapy except low molecular weight heparin are excluded)
within 30 days prior to registration

- Total bilirubin =< 1.5 x upper limit of normal (ULN) appropriate for age (except for
patients with Gilbert's syndrome, who must have a total bilirubin < 3 mg/dL) within 30
days prior to registration

- Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) or
serum glutamate pyruvate transaminase (SGPT) alanine aminotransaminase (ALT) < 2.5
upper limit of normal (ULN) appropriate for age within 30 days prior to registration

- Females of child-bearing potential must have a negative serum pregnancy test within 7
days prior to registration; exceptions: females not of child-bearing potential due to
surgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, or
surgical bilateral oophorectomy with or without hysterectomy) confirmed by medical
history; or female after menopause

- A "postmenopausal woman" is a woman meeting either of the following criteria:

- Spontaneous amenorrhea for at least 12 months, not induced by a medical
condition such as anorexia nervosa and not taking medications during the
amenorrhea that induced the amenorrhea (for example, oral contraceptives,
hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen
receptor modulators [SERMs], or chemotherapy)

- Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone
(FSH) level > 40 mIU/mL

- Females of child-bearing potential and males must agree to use highly effective
contraceptive precautions during the trial and up to 12 months following the last
dose of study treatment; a highly effective method of birth control is defined as
one that results in a low failure rate (that is, < 1% per year) when used
consistently and correctly, such as implants, injectables, combined oral
contraceptives, some intrauterine contraceptive devices (IUDs), sexual
abstinence, or a vasectomized partner

- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry

- PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA

- TP53 sequencing by NGS performed by central pathology lab

Exclusion Criteria:

- PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

- Well-differentiated liposarcoma or other low grade STS; Kaposi sarcoma, bone sarcomas,
cartilage sarcomas and gastrointestinal stromal tumor (GIST)

- Definitive clinical or radiologic evidence of metastatic disease; indeterminant lung
nodules less than 8 mm are acceptable

- The patient has history of another primary malignancy, with the exception of

- Curatively treated non-melanomatous skin cancer;

- Curatively treated cervical carcinoma in situ;

- Non-metastatic prostate cancer

- Other primary non-hematologic malignancies or solid tumor treated with curative
intent, no known active disease, and no treatment administered during the last 3
years prior to registration

- The patient has a serious cardiac condition, such as congestive heart failure; New
York Heart Association class II/ III/IV heart disease; unstable angina pectoris,
cardiac stenting within 6 months of enrollment; myocardial infarction within the last
3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or
arrhythmias that are symptomatic or require treatment

- Females who are pregnant or breastfeeding

- Prior systemic chemotherapy for the study cancer (sarcoma); note that prior
chemotherapy for a different cancer is allowable; however, unresolved toxicities from
prior anti-tumor therapy, defined as not having resolved to Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0 grade 0 or 1, or to levels dictated in
the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from
prior anti-tumor therapy that are considered irreversible [defined as having been
present and stable for > 6 months], such as ifosfamide-related proteinuria, may be
allowed if they are not otherwise described in the exclusion criteria AND there is
agreement to allow by both the investigator and sponsor)

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- Clinically significant bleeding within 4 weeks of screening, current use of warfarin,
factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be
safely discontinued 14 days prior to AMG-232 administration; Note: low molecular
weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the
inclusion criteria; subjects taking warfarin must have their INR followed closely

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AMG 232

- All subjects must agree to stop the use of all herbal medicines (e.g., St. John's
wort), and supplements, within the 10 days prior to receiving the first dose of AMG
232, and during the protocol AMG 232 treatment (weeks 1-5); subjects may renew the use
of the above at week 6; standard adult multi-vitamin is allowed

- All subjects must agree to stop the use of any known CYP3A4 substrates with narrow
therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine,
pimozide, quinidine, sirolimus, or terfanide; within the 14 days prior to receiving
the first dose of AMG 232 and during protocol AMG 232 treatment (weeks 1-5); other
medications (such as fentanyl and oxycodone) may be allowed per investigator's
assessment/evaluation

- All subjects must agree to stop the use of any known CYP2C8 substrates with a narrow
therapeutic window within the 14 days prior to receiving the first dose of AMG 232 and
during protocol AMG 232 treatment (weeks 1-5)

- All subjects are required to submit a list of medications consumed within 14 days
prior to receiving the first dose of AMG232 and during the protocol AMG232 treatment
(weeks 1-5)

- Patients with gastrointestinal (GI) tract disease causing the inability to take oral
medication, malabsorption syndrome, requirement for intravenous alimentation, prior
surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
Crohn's disease, ulcerative colitis), therefore could affect the absorption of AMG 232
at the discretion of treating physician

- Patients with active infection requiring intravenous (IV) antibiotics within 2 weeks
of registration

- Patients with known positive hepatitis B surface antigen (HepBsAg) (indicative of
chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG
(suggestive of occult hepatitis B), or detectable hepatitis C virus RNA by a
polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is
generally done by hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by
PCR if HepCAb is positive)

- Patients known to be positive for human immunodeficiency virus (HIV) are NOT excluded
from this study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
PCR-based test

- HIV testing is not required

- Treatment with medications known to cause corrected QT (QTc) interval prolongation
within 7 days of study day 1 is not permitted unless approved by the sponsor; use of
ondansetron is permitted for treatment of nausea and vomiting